Elevated plasma homocyst(e)ine is a risk factor for endothelial dysfunction and vascular disease. In late gestation, levels of homocyst(e)ine are higher in preeclamptics, as compared with normotensive pregnant women. Our objective was to determine whether homocyst(e)ine elevations precede the development of preeclampsia. We used a prospective nested case-control study to compare second trimester maternal serum homocyst(e)ine concentrations in 52 patients who developed preeeclampsia (pregnancy-induced hypertension with proteinuria) compared with 56 women who remained normotensive throughout pregnancy. Study subjects were selected from a base population of 3,042 women who provided blood samples at an average gestational age of 16 weeks and later delivered at our center. Serum homocyst(e)ine was measured by high performance liquid chromatography and electro-chemical detection. Approximately 29% of preeclamptics, as compared to 13% of controls, had homocyst(e)ine levels ?5.5 umol/L (upper decile of distribution of control values). Adjusted for maternal age, parity, and body mass-index, a second trimester elevation of homocyst(e)ine was associated with a 3.2-fold increased risk of preeclampsia (adjuster OR=3.2; 95% CI 1.1-9.2; p=0.030). There was evidence of an interaction between maternal adiposity (as indicated by her pre-pregnancy body mass index) and parity with second trimester elevations in serum homocyst(e)ine. Nulliparous women with elevated homocyst(e)ine levels experienced a 9.7-fold increased risk of preeclampsia as compared with multiparous women without homocyst(e)ine elevations (95% CI 2.1-14.1; p=0.003). Women with a higher pre-pregnancy body mass index (?21.4 kg/m2, or upper 50th percentile) and who also had elevated homocyst(e)ine levels, as compared with leaner women without homocyst(e)ine elevations, were 6.9 times more likely to later develop preeclampsia (95% CI 1.4-32.1; p=0.016). Our findings are consistent with other indications of vascular dysfunction predating clinical preeclampsia. Studies designed to examine the effect of dietary and/or pharmacological mediators of homocyst(e)ine metabolism in preeclampsia are warranted. FUNDING NIH HD/HL-32562 PUBLICATIONS None